The specificity of HIV-1 for human cells precludes virus infection in most mammalian species. This limits the use of small animal models for the studies of HIV-1 neuropathogenesis. Existing models that use human xenografts into rodents have significant limitations. We hypothesize that NOD/scid-?c-/- mice transplanted with -/- CD34+ hematopoietic stem cells will engraft human macrophages/microglia in the brain. These humanized animals are able to mount chronic HIV-1 infection and develop human adaptive immune responses. We will investigate the establishment of a human cell network in mouse brain, their susceptibility to HIV-1 and the mechanisms involved in the control of HIV-1 replication (both in the peripheral lymphoid tissues and in the brain). We will also explore the mechanisms of neuronal damage and correlate them with known factors involved in human HIV-1-associated brain pathology. To validate this model we will use two approaches: depletion of human CD8+ cells to diminish control of viral replication, and stimulation of anti-viral immunity by human CD40L. These experiments will explore the application of the model and unmask possible restrictions for its use. It will be the best known small animal model as of today, to study HIV-1 pathogenesis, therapeutics and vaccine development in a novel human immune system setting. The specificity of HIV-1 for human cells precludes virus infection in most mammalian species and limits the use of small animal models for the studies of HIV-1 neuropathogenesis. We will investigate the establishment of a human cell network in the brain of NOD/scid-?c-/- mice transplanted with human CD34+ hematopoietic stem -/- cells, their susceptibility to HIV-1, the mechanisms involved in the control of HIV-1 replication and neuronal damage. This model will be the best suited for NeuroAIDS research. [unreadable] [unreadable] [unreadable]